This is a revised proposal to study the genetics of opioid dependence using linkage analysis of a collection of 460 small nuclear families, each including an affected sibling pair. The clinical work would take place at four university-based programs in Southern New England, and the laboratory and statistical work at Yale and Boston Universities, respectively. The objective of this revised proposal remains an attempt to identify chromosomal regions containing genes predisposing to opioid dependence (OD). The aims of the plan are to collect a set of 460 small nuclear families, primarily affected sibling pairs, and (when possible) additional siblings and parents; complete a 10 cM genome-wide scan using 400 equally spaced STR markers; use affected sib-pair (ASP) and transmission-disequilibrium test (TDT) approaches to analyze the marker data for linkage to OD; and use an additional marker set for fine mapping (approximately 2 cM) of promising genomic regions. A secondary analysis would assess the impact of comorbid disorders and personality dimensions in further refining the OD phenotype in establishing the genetics of OD. Proband affection would be defined as opioid dependence without antisocial personality disorder (ASPD) according to DSM-IV diagnostic criteria as ascertained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). The principal method of linkage analysis will be sibling pair linkage. Animal and human adoption, twin and family studies support the contention that the particular phenotype chosen for study is genetically influenced to an extent that the investigators can reasonably expect to be able to map related genes. Exclusion of subjects with comorbid ASPD would allow for a more genetically homogeneous clinical sample and aid this effort. The clinical diagnostic data and DNA collected as part of the proposed study would be shared with other investigators to support future mapping efforts in psychiatric and addictive disorder genetics. The proposed revised project represents the first large-scale linkage study of drug dependence. Successful completion of the proposed project would provide information that would, eventually, advance an understanding of the mechanisms of opioid dependence, and possibly lead to new ways to treat this pervasive and costly societal problem.